Leaky gut, circulating immune complexes, arthralgia, and arthritis in IBD: coincidence or inevitability?

Abstract

Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.

Keywords: antigen-antibody complex; arthritis; complement; inflammatory bowel diseases; leaky gut; mitochondrial dysfunction.

Figure 1

Illustration depicting the comparative analysis of C1q, IgG, IgA, and IgM levels between untreated IBD patients and individuals without chronic diseases: (A) Plasma levels of complement C1q significantly increased in patients with IBD (22.49, n=40) compared with controls (18.13, n=40). (B) Elevated IgG plasma levels were observed in IBD patients (14.44, n=40) compared with controls (11.25, n=40). (C) Patients with IBD exhibited higher concentrations of IgA in plasma (2.66, n=40) compared with controls (2.28, n=40). (D) Plasma levels of IgM showed no significant difference between IBD patients (1.23, n=40) and controls (0.86, n=40). Statistical significance is indicated as follows: ns indicates p > 0.05, * signifies p < 0.05, and **** denotes p < 0.0001 vs. the control group. (Unpaired t test with Welch’s correction of C1q and IgG; Mann Whitney test of IgA and IgM). Laboratory test results were collected from medical records of patients with IBD and age- and sex-matched healthy participants at the China-Japan Union Hospital of Jilin University between June 2021 and June 2022. Patients diagnosed with IBD had experienced symptoms for more than 6 months prior to hospital admission. In the experimental group, 47.5% of participants were male, whereas in the control group, the proportion was 35%. The mean ages of the experimental and control groups were 44.5 and 47.1 years, respectively. Exclusion criteria for patients included not receiving immunotherapy, absence of malignancy diagnosis, and normal body temperature. Healthy controls without any known diseases were enrolled and paired accordingly. The study adhered to the principles outlined in the Helsinki Declaration and the Rules of Good Clinical Practice. Approval was obtained from the Ethics Committee of the China-Japan Union Hospital of Jilin University, and the study was registered in the Chinese Clinical Trial Registry (No. 2023053016). All participants provided written informed consent before participation.

Figure 2

Inflammatory bowel disease leads to a compromised gut barrier, allowing the entry of microbiota and their products into gut tissues. This figure illustrates the interaction between intestinal epithelial cells, complement proteins (C1q, C3, factor B), IgG, antigen-presenting cells, T cells, and B cells. B cells capture microbial fragments, leading to their breakdown, while helper T cells activate B cells. This activation transforms B cells into plasma cells, producing antibodies. Additionally, the complement system forms membrane attack complexes (MAC) that adhere to affected cells and cause destruction. Some MAC structures attach to gut blood vessel walls, amplifying inflammation. The figure also highlights the potential for antibody-microbe complexes to travel through the bloodstream, potentially affecting joints. Created with BioRender.com.